Stress is a fundamental part of life for all cells and organisms and dealing successfully with stress facilitates survival in cells and whole organisms. Oncogenic transformation creates substantial intrinsic cell stress (e.g. metabolic, proteotoxic, DNA damage stresses). Tumor cells respond to intrinsic stress in numerous, highly conserved ways, some of which facilitate cell survival. Tumor growth may also cause changes in the microenvironment in which malignant cells develop - changes which add additional extrinsic stress factors (e.g. inflammation, hypoxia, high interstitial fluid pressure, nutritional deprivation, low pH). Finally, anticancer therapy adds to both intrinsic cell stress and may change the tumor microenvironment, modifying those stress factors, too. Cell Stress and Biophysical Therapies (CSBT) Program members are committed to understanding the mechanisms and responses in tumor cells which help them evade anticancer therapies as well as host antitumor responses. The overall goal of the CSBT Program is to identify, understand and exploit tumor cell stress and microenvironment mechanisms, and to use this to develop novel therapies. Members share interest in the imaging and therapy potential for modalities such as light, heat and ionizing radiation energies. There are three research themes in the program and each integrates basic, translational and clinical science: 1) Understanding intrinsic cancer cell stress mechanisms, 2) Understanding stress mechanisms in the host/tumor microenvironment and 3) Protecting normal cells/tissues from therapy-induced damage. The Program is co-led by Drs. Andrei Gudkov and Elizabeth Repasky each of whom has successful and complimentary research programs that span the themes of the program. Retreats and monthly program meetings focus on basic and translational research and discussions of new collaborations and clinical trial opportunities. Since the last review, the laboratories of the CSBT members have moved into closer proximity in the newly constructed Center for Genetics and Pharmacology. The program is comprised of 20 members from 8 different RPCI departments. Current annual total peer-reviewed program funding is $S.4M, of which $2.6M is NCI, and the total extramural research funding is $6.9M. Of the 353 publications of CSBT members over the last funding cycle, 21% are intra-programmatic and 20% are inter-programmatic. Importantly, the number of high impact papers (Impact Factor>10) has significantly increased (10 to 33) while at the same time, the major goal of developing new clinical trials emerging from research developed within the CSBT Program continues to be very strong and successful.